This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In our laboratory we have developed a systematic approach to the synthesis of functionalized macromolecules with programmable three-dimensional shapes (Molecular Lego). In collaboration with the Edgewood Chemical Biology Center (ARMY) we are developing sensors for organophosphorous nerve agents using Molecular Lego. The molecules that we are designing consist of two 2.5 nanometer rods connected by a flexible hinge and on each end of the molecule is a hydroxylamide nucleophile that can react with an organophosphorous group. The idea is that the sensor will normally be in an open position, extended up to 5 nm in length and when it comes in contact with an organophosphorous molecule, one hydroxylamide will react with the organophosphorous group, creating a covalent adduct. Then the other end will be able to fold over and react with the organophosphorous group a second time, creating a compact macrocycle. We will detect the large conformational change that results from this reaction and use this as a sensor. I have written a software package (~100,000 lines of C++ and Python) that automatically builds millions of possible sensors and scores them based on well they can carry out their sensing function. The software will compile with GNU